Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with an incidence of 1 in 10'000 (approx. 30'000 patients in USA). HD is not prevalent to any particular population, race or ethnic group, and both genders are affected. HD manifests in middle age (30-50 years) with jerking, uncontrollable movement of the limbs, trunk and face followed by progressive loss of mental abilities and development of psychiatric problems. The disease continues without remission over 10 to 25 years and is ultimately terminal.
The cause of the disease is an expansion of CAG repeats in exon 1 of the gene coding for the protein huntingtin. This expansion produces a mutated protein (mHTT) with a polyglutamine repeat within the amino terminus. mHTT and its proteolytic N-terminal fragments accumulate in intracellular aggregates and have been shown to interfere with the transcriptional machinery of the cell.
Transcriptional dysregulation is the first detectable change in HD and it is observed in both human and animal correlates of disease. Modulation of transcriptional activity can be achieved via the inhibition of histone deacetylase enzymes a family of 11 isotypes further classified into sub-families: HDAC1,2,3,8 (Class I); HDAC4,5,7,9 (Class IIa), HDAC6,10 (Class IIb) and HDAC11 (Class IV). HDAC inhibition can restore the balance and a pan-HDAC inhibitor (SAHA) has been found efficacious in Drosophila and mouse assays for Huntington's pathology (Hockly et al., PNAS (2003) 100:2041; Kazantsev A G, Thompson L M., Nat Rev Drug Discov. (2008) 7:854-68). As SAHA is a non-selective inhibitor of all HDACs Class I, IIa+IIb and IV sub-families it is not possible to determine through which isotype/sub-family the beneficial effects are mediated.
Recently the individual role of members of the Class IIa sub-family (HDAC4,5,7,9) was investigated by knocking-down the respective isotypes by genetic crossing with the R6/2 mouse, a genetically engineered mouse mimicking the human HD pathology (Mielcarek M. et al., J. Neurology, Neurosurgery and Psychiatry (2009) 79:A8). The resulting double transgenic mice strains for which HDAC 5, HDAC 7 or HDAC 9 were knocked-down did not show any improvement of the R6/2 phenotype whereas the reduction in HDAC4 expression levels improved the motor impairment phenotype of the R6/2 mice.
HDAC4 inhibition therefore provides a potential opportunity for pharmaceutical intervention and treatment of Huntington's disease.
Class IIa HDACs are also expressed in skeletal muscle and are expressed at a lower level in slow-twitching muscle compared to fast-twitching muscle. Deletion of any combination of four alleles of HDAC4, 5 and 9 leads to more slow-fiber gene expression, which in turn leads to enhanced running endurance (Potthoff et al., J. Clin. Invest. (2007) 117, 2459-2467). Furthermore, HDAC4 gene expression is highly upregulated in muscle after denervation/casting/hindlimb suspension (Bodine et al., Science (2001) 294, 1704-1708; Cohen et al. JBC (2007) 282(46):33752-9). HDAC4 inhibits the expression of FGFBP1, which interacts with FGF7/10/22 and promotes reinnervation (Williams et al., Science (2009) 326, 1549-1554). Upon denervation, increased HDAC4 expression also represses the expression of Dach2, which in turn leads to increased expression of myogenin. Myogenin upregulates the expression of the two E3 ubiquitin ligases that are required for muscle atrophy. Denervated mice lacking HDAC4 (muscle specific knockout) or HDAC5 demonstrated a 30% loss in muscle weight compared to the 50% loss of muscle mass in WT mice, while mice lacking both HDAC4 and HDAC5 demonstrated only a 10% decrease in muscle weight (Moresi et al., Cell (2010) 143, 35-45).
Inhibition of HDAC4 thus also provides a potential method for treating muscle atrophy.
In addition, a very recent publication has shown a pivotal role for HDAC Class IIa in the regulation of glucose homeostasis (Mihaylova M M, et al., Cell (2011) 145, 607-21). In a mouse model for hyperglycemia (ob/ob mouse) reduction of Class IIa HDACs using shRNAs against HDAC4, 5 and 7 has been shown to lower blood glucose and increase glycogen storage. Furthermore, reduction of Class IIa HDACs in a mouse model for type 2 diabetes (high fat diet mouse) significantly improves hyperglycemia.
Use of a pharmacological agent to reduce the activity of HDAC4 may therefore also provide a useful therapeutic intervention for the treatment of diabetes/metabolic syndrome.
Class I HDACs can de-acetylate histones and other transcription factors. Inhibition of class I HDACs can lead to inhibition of proliferation, induce terminal cell differentiation and/or apoptosis, and induction or repression of gene expression in cells. Class I HDAC inhibitors would therefore be of most use in cancer therapy (Davie J R, J Nutr (2003 July) 133 (7 Suppl), 2485S-2493S). In contrast, class II HDACs do not target histones. It would therefore be advantageous to provide Class IIa-selective HDAC4 inhibitors for the treatment of Huntington's disease, muscle atrophy or diabetes/metabolic syndrome which have low inhibitory activity against Class I HDACs.
The present invention thus relates to novel trifluoromethyl-oxadiazole derivatives having Class IIa-selective HDAC4 inhibitory activity and their medical use, particularly in the treatment of Huntington's disease, muscle atrophy and diabetes/metabolic syndrome.